Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of the glomerular endothelium in albumin handling

Nature Reviews Nephrology volume 9, pages 717–725 (2013)Cite this article

Subjects

Abstract

The unique permeability characteristics of the glomerular capillary wall depend on its three-layer structure, consisting of endothelial cells, the basement membrane and podocytes. These components form the glomerular filtration barrier (GFB). That albuminuria may occur in the absence of changes in podocyte foot processes suggests that GFB components other than podocytes have essential roles in albumin handling. The endothelium forms the first part of the GFB and is characterized by fenestrations—transcellular holes that are filled with endothelial glycocalyx, a hydrated mesh principally comprised of proteoglycans. The glycocalyx and adsorbed plasma constituents form the endothelial surface layer (ESL). Human and animal studies have shown that the glomerular ESL restricts macromolecule passage and ensures that plasma albumin is largely excluded from the GFB. The glomerular endothelium is also likely to indirectly influence glomerular albumin handling by modifying podocyte behaviour. These modifications may occur physiologically through soluble mediators and/or pathologically through increased exposure of podocytes to plasma components as a consequence of ESL dysfunction. The importance of the glomerular endothelium and ESL in albumin handling also sheds light on the relationship between albuminuria and vascular disease. The therapeutic potential that this relationship offers will become evident with better understanding of the structure, composition and regulation of the glycocalyx.

Key Points

  • The glomerular filtration barrier (GFB) functions as a whole with each layer making an important contribution

  • Albuminuria can occur in the absence of changes in podocyte foot processes, confirming that other GFB components have essential roles in albumin handling

  • The glomerular endothelium is characterized by fenestrations (transcellular holes essential for filtration function) and a surface glycocalyx that extends over the fenestrations

  • The glomerular endothelial surface layer (ESL) consists of a surface-bound glycocalyx and adsorbed plasma components; dysfunction of the ESL contributes to increased glomerular permeability in disease

  • Cell-to-cell communication has an important role in glomerular homeostasis; glomerular endothelial cell-to-podocyte communication is likely to regulate the podocyte contribution to glomerular albumin handling in health and disease

  • Dysfunction of the glomerular endothelial glycocalyx is an attractive therapeutic target that links albuminuria to systemic vascular disease and potentially helps to explain why albuminuria is a risk factor for cardiovascular disease

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Under normal haemodynamic conditions albumin is largely excluded from the glomerular filtration barrier.
Figure 2: The role of the ESL in the glomerular filtration barrier.

Similar content being viewed by others

References

  1. Neal, C. R., Crook, H., Bell, E., Harper, S. J. & Bates, D. O. Three-dimensional reconstruction of glomeruli by electron microscopy reveals a distinct restrictive urinary subpodocyte space. J. Am. Soc. Nephrol. 16, 1223–1235 (2005).

    Article  PubMed  Google Scholar 

  2. Norden, A. G. et al. Glomerular protein sieving and implications for renal failure in Fanconi syndrome. Kidney Int. 60, 1885–1892 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Michel, C. C. & Curry, F. E. Microvascular permeability. Physiol. Rev. 79, 703–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Pavenstadt, H., Kriz, W. & Kretzler, M. Cell biology of the glomerular podocyte. Physiol. Rev. 83, 253–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Haraldsson, B. & Sorensson, J. Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier. News Physiol. Sci. 19, 7–10 (2004).

    PubMed  Google Scholar 

  6. Haraldsson, B., Nystrom, J. & Deen, W. M. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol. Rev. 88, 451–487 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Ryan, G. B. & Karnovsky, M. J. Distribution of endogenous albumin in the rat glomerulus: role of hemodynamic factors in glomerular barrier function. Kidney Int. 9, 36–45 (1976).

    Article  CAS  PubMed  Google Scholar 

  8. Lund, U. et al. Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys. Am. J. Physiol. Renal Physiol. 284, F1226–F1234 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Rippe, C., Asgeirsson, D., Venturoli, D., Rippe, A. & Rippe, B. Effects of glomerular filtration rate on Ficoll sieving coefficients (θ) in rats. Kidney Int. 69, 1326–1332 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Rippe, B. What is the role of albumin in proteinuric glomerulopathies? Nephrol. Dial. Transplant. 19, 1–5 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605–12608 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yoshioka, T., Ichikawa, I. & Fogo, A. Reactive oxygen metabolites cause massive, reversible proteinuria and glomerular sieving defect without apparent ultrastructural abnormality. J. Am. Soc. Nephrol. 2, 902–912 (1991).

    CAS  PubMed  Google Scholar 

  14. Friden, V. et al. The glomerular endothelial cell coat is essential for glomerular filtration. Kidney Int. 79, 1322–1330 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Davis, B. et al. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J. Am. Soc. Nephrol. 18, 2320–2329 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Macconi, D. et al. Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats. J. Am. Soc. Nephrol. 11, 477–489 (2000).

    CAS  PubMed  Google Scholar 

  17. Stillman, I. E. & Karumanchi, S. A. The glomerular injury of preeclampsia. J. Am. Soc. Nephrol. 18, 2281–2284 (2007).

    Article  PubMed  Google Scholar 

  18. Pagtalunan, M. E. et al. Podocyte loss and progressive glomerular injury in type II diabetes. J. Clin. Invest. 99, 342–348 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Branten, A. J., van den Born, J., Jansen, J. L., Assmann, K. J. & Wetzels, J. F. Familial nephropathy differing from minimal change nephropathy and focal glomerulosclerosis. Kidney Int. 59, 693–701 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. van den Berg, J. G., van den Bergh Weerman, M. A., Assmann, K. J., Weening, J. J. & Florquin, S. Podocyte foot process effacement is not correlated with the level of proteinuria in human glomerulopathies. Kidney Int. 66, 1901–1906 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Kriz, W., Shirato, I., Nagata, M., Lehir, M. & Lemley, K. V. The podocyte's response to stress: the enigma of foot process effacement. Am. J. Physiol. Renal Physiol. 304, F333–F347 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Levick, J. R. & Michel, C. C. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87, 198–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Satchell, S. C. & Tooke, J. E. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 51, 714–725 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Satchell, S. C. & Braet, F. Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am. J. Physiol. Renal Physiol. 296, F947–F956 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ichimura, K., Stan, R. V., Kurihara, H. & Sakai, T. Glomerular endothelial cells form diaphragms during development and pathologic conditions. J. Am. Soc. Nephrol. 19, 1463–1471 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Deen, W. M., Lazzara, M. J. & Myers, B. D. Structural determinants of glomerular permeability. Am. J. Physiol. Renal Physiol. 281, F579–F596 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Satchell, S. C., Anderson, K. L. & Mathieson, P. W. Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. J. Am. Soc. Nephrol. 15, 566–574 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Satchell, S. C. et al. Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int. 69, 1633–1640 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Sorensson, J. et al. Glomerular endothelial fenestrae in vivo are not formed from caveolae. J. Am. Soc. Nephrol. 13, 2639–2647 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Rostgaard, J. & Qvortrup, K. Electron microscopic demonstrations of filamentous molecular sieve plugs in capillary fenestrae. Microvasc. Res. 53, 1–13 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Hjalmarsson, C., Johansson, B. R. & Haraldsson, B. Electron microscopic evaluation of the endothelial surface layer of glomerular capillaries. Microvasc. Res. 67, 9–17 (2004).

    Article  PubMed  Google Scholar 

  32. Dane, M. J. et al. Glomerular endothelial surface layer acts as a barrier against albumin filtration. Am. J. Pathol. 182, 1532–1540 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Levick, J. R. & Smaje, L. H. An analysis of the permeability of a fenestra. Microvasc. Res. 33, 233–256 (1987).

    Article  CAS  PubMed  Google Scholar 

  34. Salmon, A. H. & Satchell, S. C. Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability. J. Pathol. 226, 562–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A. & oude Egbrink, M. G. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 454, 345–359 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weinbaum, S., Tarbell, J. M. & Damiano, E. R. The structure and function of the endothelial glycocalyx layer. Annu. Rev. Biomed. Eng. 9, 121–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Pries, A. R., Secomb, T. W. & Gaehtgens, P. The endothelial surface layer. Pflugers Arch. 440, 653–666 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Oohira, A., Wight, T. N. & Bornstein, P. Sulfated proteoglycans synthesized by vascular endothelial cells in culture. J. Biol. Chem. 258, 2014–2021 (1983).

    CAS  PubMed  Google Scholar 

  39. Lindblom, A., Carlstedt, I. & Fransson, L. A. Identification of the core proteins in proteoglycans synthesized by vascular endothelial cells. Biochem. J. 261, 145–153 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Griesmacher, A., Hennes, R., Keller, R. & Greiling, H. Proteoglycans from human umbilical vein endothelial cells. Eur. J. Biochem. 168, 95–101 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. Avasthi, P. S. & Koshy, V. The anionic matrix at the rat glomerular endothelial surface. Anat. Rec. 220, 258–266 (1988).

    Article  CAS  PubMed  Google Scholar 

  42. Singh, A. et al. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J. Am. Soc. Nephrol. 18, 2885–2893 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Singh, A. et al. High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am. J. Physiol. Renal Physiol. 300, F40–F48 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Foster, R. R. et al. Glycosaminoglycan regulation by VEGFA and VEGFC of the glomerular microvascular endothelial cell glycocalyx in vitro. Am. J. Pathol. 183, 604–616 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Squire, J. M. et al. Quasi-periodic substructure in the microvessel endothelial glycocalyx: a possible explanation for molecular filtering? J. Struct. Biol. 136, 239–255 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Arkill, K. P. et al. Similar endothelial glycocalyx structures in microvessels from a range of mammalian tissues: evidence for a common filtering mechanism? Biophys. J. 101, 1046–1056 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bankston, P. W. & Milici, A. J. A survey of the binding of polycationic ferritin in several fenestrated capillary beds: indication of heterogeneity in the luminal glycocalyx of fenestral diaphragms. Microvasc. Res. 26, 36–48 (1983).

    Article  CAS  PubMed  Google Scholar 

  48. Salmon, A. H. et al. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J. Am. Soc. Nephrol. 23, 1339–1350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ebong, E. E., Macaluso, F. P., Spray, D. C. & Tarbell, J. M. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler. Thromb. Vasc. Biol. 31, 1908–1915 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Simionescu, M., Simionescu, N., Silbert, J. E. & Palade, G. E. Differentiated microdomains on the luminal surface of the capillary endothelium. II. Partial characterization of their anionic sites. J. Cell Biol. 90, 614–621 (1981).

    Article  CAS  PubMed  Google Scholar 

  51. Zeng, Y., Ebong, E. E., Fu, B. M. & Tarbell, J. M. The structural stability of the endothelial glycocalyx after enzymatic removal of glycosaminoglycans. PLoS ONE 7, e43168 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fried, T. A., McCoy, R. N., Osgood, R. W. & Stein, J. H. Effect of albumin on glomerular ultrafiltration coefficient in isolated perfused dog glomerulus. Am. J. Physiol. 250, F901–F906 (1986).

    CAS  PubMed  Google Scholar 

  53. Schnitzer, J. E. & Pinney, E. Quantitation of specific binding of orosomucoid to cultured microvascular endothelium: role in capillary permeability. Am. J. Physiol. 263, H48–H55 (1992).

    CAS  PubMed  Google Scholar 

  54. Haraldsson, B. S., Johnsson, E. K. & Rippe, B. Glomerular permselectivity is dependent on adequate serum concentrations of orosomucoid. Kidney Int. 41, 310–316 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Lennon, R. et al. Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes. J. Am. Soc. Nephrol. 19, 2140–2149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Singh, A. et al. Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx. PLoS ONE 8, e55852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jeansson, M. & Haraldsson, B. Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes. J. Am. Soc. Nephrol. 14, 1756–1765 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Jeansson, M. & Haraldsson, B. Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier. Am. J. Physiol. Renal Physiol. 290, F111–F116 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Gelberg, H., Healy, L., Whiteley, H., Miller, L. A. & Vimr, E. In vivo enzymatic removal of α2 6-linked sialic acid from the glomerular filtration barrier results in podocyte charge alteration and glomerular injury. Lab. Invest. 74, 907–920 (1996).

    CAS  PubMed  Google Scholar 

  60. Bakker, W. W. et al. Protease activity of plasma hemopexin. Kidney Int. 68, 603–610 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Meuwese, M. C. et al. Endothelial surface layer degradation by chronic hyaluronidase infusion induces proteinuria in apolipoprotein E-deficient mice. PLoS ONE 5, e14262 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jeansson, M., Bjorck, K., Tenstad, O. & Haraldsson, B. Adriamycin alters glomerular endothelium to induce proteinuria. J. Am. Soc. Nephrol. 20, 114–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Remuzzi, A., Puntorieri, S., Battaglia, C., Bertani, T. & Remuzzi, G. Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J. Clin. Invest. 85, 541–549 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kuwabara, A., Satoh, M., Tomita, N., Sasaki, T. & Kashihara, N. Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats. Diabetologia 59, 2056–2065 (2010).

    Article  CAS  Google Scholar 

  65. Adembri, C. et al. Sepsis induces albuminuria and alterations in the glomerular filtration barrier: a morphofunctional study in the rat. Crit. Care 15, R277 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Jeansson, M., Granqvist, A. B., Nystrom, J. S. & Haraldsson, B. Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice. Diabetologia 49, 2200–2209 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Satoh, M. et al. In vivo visualization of glomerular microcirculation and hyperfiltration in streptozotocin-induced diabetic rats. Microcirculation 17, 103–112 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Xu, C. et al. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney Int. http://dx.doi.org/10.1038/ki.2013.286.

  69. Gil, N. et al. Heparanase is essential for the development of diabetic nephropathy in mice. Diabetes 61, 208–216 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Nieuwdorp, M. et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55, 1127–1132 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Nieuwdorp, M. et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55, 480–486 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Broekhuizen, L. N. et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia 53, 2646–2655 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Deckert, T. et al. Size and charge selectivity of glomerular filtration in type 1 (insulin-dependent) diabetic patients with and without albuminuria. Diabetologia 36, 244–251 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. Lemley, K. V. et al. Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus. J. Am. Soc. Nephrol. 11, 2095–2105 (2000).

    CAS  PubMed  Google Scholar 

  75. Schmidt, E. P. et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat. Med. 18, 1217–1223 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Zuurbier, C. J., Demirci, C., Koeman, A., Vink, H. & Ince, C. Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells. J. Appl. Physiol. 99, 1471–1476 (2005).

    Article  PubMed  Google Scholar 

  77. Rubio-Gayosso, I., Platts, S. H. & Duling, B. R. Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 290, H2247–H2256 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Nieuwdorp, M. et al. Tumor necrosis factor-α inhibition protects against endotoxin-induced endothelial glycocalyx perturbation. Atherosclerosis 202, 296–303 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Henry, C. B. & Duling, B. R. TNF-α increases entry of macromolecules into luminal endothelial cell glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 279, H2815–H2823 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Tumova, S., Woods, A. & Couchman, J. R. Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. Int. J. Biochem. Cell Biol. 32, 269–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Multhaupt, H. A. & Couchman, J. R. Heparan sulfate biosynthesis: methods for investigation of the heparanosome. J. Histochem. Cytochem. 60, 908–915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schwartz, N. Biosynthesis and regulation of expression of proteoglycans. Front. Biosci. 5, D649–D655 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Bishop, J. R., Schuksz, M. & Esko, J. D. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446, 1030–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Salmon, A. H. et al. Angiopoietin-1 alters microvascular permeability coefficients in vivo via modification of endothelial glycocalyx. Cardiovasc. Res. 83, 24–33 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Satchell, S. C., Anderson, K. L., Tooke, J. E., Bates, D. O. & Mathieson, P. W. Angiopoietin 1 increases the integrity of human glomerular endothelial cell monolayers. J. Am. Soc. Nephrol. 13, 496A (2002).

    Google Scholar 

  86. Foster, R. R. et al. VEGF-C promotes survival in podocytes. Am. J. Physiol. Renal Physiol. 291, F196–F207 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Foster, R. R. et al. Vascular endothelial growth factor-C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium. Am. J. Pathol. 173, 938–948 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sison, K. et al. Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J. Am. Soc. Nephrol. 21, 1691–1701 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Traub, O. & Berk, B. C. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler. Thromb. Vasc. Biol. 18, 677–685 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Segal, S. S. Regulation of blood flow in the microcirculation. Microcirculation 12, 33–45 (2005).

    Article  PubMed  Google Scholar 

  93. Forbes, M. S., Thornhill, B. A., Park, M. H. & Chevalier, R. L. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Am. J. Pathol. 170, 87–99 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhao, H. J. et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J. Am. Soc. Nephrol. 17, 2664–2669 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Nakagawa, T. et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J. Am. Soc. Nephrol. 18, 539–550 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Kanetsuna, Y. et al. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am. J. Pathol. 170, 1473–1484 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kidokoro, K. et al. Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy. J. Am. Soc. Nephrol. 24, 1139–1150 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Furusu, A. et al. Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int. 53, 1760–1768 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Heeringa, P. et al. Renal expression of endothelial and inducible nitric oxide synthase, and formation of peroxynitrite-modified proteins and reactive oxygen species in Wegener's granulomatosis. J. Pathol. 193, 224–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Heeringa, P., Steenbergen, E. & van Goor, H. A protective role for endothelial nitric oxide synthase in glomerulonephritis. Kidney Int. 61, 822–825 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Zanchi, A. et al. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int. 57, 405–413 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Slater, S. C. et al. Chronic exposure to laminar shear stress induces Kruppel-like factor 2 in glomerular endothelial cells and modulates interactions with co-cultured podocytes. Int. J. Biochem. Cell Biol. 44, 1482–1490 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Tarbell, J. M. & Ebong, E. E. The endothelial glycocalyx: a mechano-sensor and transducer. Sci. Signal. 1, pt8 (2008).

    Article  PubMed  Google Scholar 

  104. Williams, M. E. Diabetic nephropathy: the proteinuria hypothesis. Am. J. Nephrol. 25, 77–94 (2005).

    Article  PubMed  Google Scholar 

  105. Morigi, M. et al. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am. J. Pathol. 166, 1309–1320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Akilesh, S. et al. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc. Natl Acad. Sci. USA 105, 967–972 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  107. George, M. et al. Renal thrombotic microangiopathy in mice with combined deletion of endocytic recycling regulators EHD3 and EHD4. PLoS ONE 6, e17838 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hillege, H. L. et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106, 1777–1782 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Matsushita, K. et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chappell, D. et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology 107, 776–784 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Becker, B. F., Chappell, D., Bruegger, D., Annecke, T. & Jacob, M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc. Res. 87, 300–310 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Bristol, Academic Renal Unit, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK

    Simon Satchell

Authors
  1. Simon Satchell
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Satchell, S. The role of the glomerular endothelium in albumin handling. Nat Rev Nephrol 9, 717–725 (2013). https://doi.org/10.1038/nrneph.2013.197

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.197

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing